Dapagliflozin Mitigates Hepatic and Systemic Metabolic Dysregulation in Experimental Diabetes: A Systematic Review and Meta-analysis
Description
Background: The escalating global burden of diabetes mellitus (DM) is characterized by significant dysregulation in lipid and glucose homeostasis, ultimately precipitating severe multi-organ complications, including metabolic dysfunction-associated steatotic liver disease (MASLD), coronary artery disease (CAD), atherosclerosis, neuropathy, nephropathy, and retinopathy. Despite the abundance of clinical studies revealing pleiotropic effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, in mitigating these metabolic and vascular sequelae, the preclinical analyses studying the underlying molecular and pathophysiologic mechanisms remain insufficient. Methods: The review protocol, including the designed search strategy, inclusion/exclusion criteria, and statistical methodology, was officially registered on the Open Science Framework (OSF) registry (Registration DOI: 10.17605/OSF.IO/57TEM). A comprehensive systematic search of relevant preclinical studies was conducted within PubMed, Web of Science, Scopus, Cochrane Library, Wiley Online Library, and Google Scholar. Following independent screening and data extraction, the quality of the included studies and risk of bias were thoroughly judged using the SYRCLE tool. Quantitative data synthesis and meta-analyses were achieved using RevMan 5.4 and Comprehensive Meta-Analysis (CMA) V3 software. Results: The current meta-analysis synthesized data from 16 preclinical studies comprising 1,259 animals. Compared to untreated disease models, dapagliflozin-treated groups yielded a highly significant reduction of both hepatic steatosis and systemic dyslipidemia, including intrahepatic triglycerides, intrahepatic cholesterol, serum triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein (LDL). Beyond lipid-mitigation, dapagliflozin exerted profound anti-inflammatory and anti-oxidative effects. It significantly suppressed the hepatic expression of key pro-inflammatory cytokines, including tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6), interleukin-1 β (IL1-β), and lipid peroxidation marker, Malondialdehyde (MDA), while concurrently upregulating the endogenous antioxidants, including glutathione (GSH) and superoxide dismutase (SOD). Conclusion: Beyond glycemic control, our meta-analysis confirms that dapagliflozin delivers comprehensive multi-organ protection against diabetic complications through significant synergistic concomitant lipid-modulating, anti-inflammatory, and anti-oxidative mechanisms
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Institutions
- Al-Ahliyya Amman UniversityAmman, Amman